Characterization of a Tumor-Associated Activating Mutation of the p110β PI 3-kinase

PLoS One. 2013 May 29;8(5):e63833. doi: 10.1371/journal.pone.0063833. Print 2013.

Abstract

The PI3-kinase pathway is commonly activated in tumors, most often by loss of PTEN lipid phosphatase activity or the amplification or mutation of p110α. Oncogenic mutants have commonly been found in p110α, but rarely in any of the other catalytic subunits of class I PI3-kinases. We here characterize a p110β helical domain mutation, E633K, first identified in a Her2-positive breast cancer. The mutation increases basal p110β activity, but does not affect activation of p85/p110β dimers by phosphopeptides or Gβγ. Expression of the mutant causes increases in Akt and S6K1 activation, transformation, chemotaxis, proliferation and survival in low serum. E633 is conserved among class I PI3 Ks, and its mutation in p110β is also activating. Interestingly, the E633K mutant occurs near a region that interacts with membranes in activated PI 3-kinases, and its mutation abrogates the requirement for an intact Ras-binding domain in p110β-mediated transformation. We propose that the E633K mutant activates p110β by enhancing its basal association with membranes. This study presents the first analysis of an activating oncogenic mutation of p110β.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution*
  • Animals
  • Blotting, Western
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Cell Membrane / metabolism
  • Cell Movement / genetics
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / genetics*
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Enzyme Activation / genetics
  • Female
  • HEK293 Cells
  • Humans
  • Liposomes / metabolism
  • Mice
  • Mutation*
  • NIH 3T3 Cells
  • Phosphotransferases / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sequence Homology, Amino Acid
  • Sf9 Cells

Substances

  • Liposomes
  • Phosphotransferases
  • Class Ia Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1